Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia
| Autor: | Robin L. Cotter, Michael R. Thylin, Jialin Charlie Zheng, Jennifer M. Swartz, Douglas Niemann, Robin B. Shepard, Anuja Ghorpade, Yong-Chun Zeng, Yuri Persidsky, Myhanh Che, Howard E. Gendelman, Huangui Xiong, Harris A. Gelbard |
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| Rok vydání: | 1999 |
| Předmět: |
Receptors
CXCR4 AIDS Dementia Complex G protein Immunology Gene Expression Caspase 3 Apoptosis Biology HIV Envelope Protein gp120 Hippocampus Synaptic Transmission Calcium in biology Monocytes Fetus medicine In Situ Nick-End Labeling Immunology and Allergy Animals Humans RNA Messenger Cells Cultured Cell Nucleus Neurons Reverse Transcriptase Polymerase Chain Reaction Macrophages Neurotoxicity Excitatory Postsynaptic Potentials medicine.disease Chemokine CXCL12 Cell biology Rats Microscopy Electron Neurology Biochemistry Astrocytes HIV-1 Calcium Neurology (clinical) Signal transduction Oligonucleotide Probes Neural development Chemokines CXC Intracellular Signal Transduction |
| Zdroj: | Journal of neuroimmunology. 98(2) |
| ISSN: | 0165-5728 |
| Popis: | The mechanism(s) by which HIV-1 affects neural injury in HIV-1-associated dementia (HAD) remains unknown. To ascertain the role that cellular and viral macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neurons, is both a part of neural development and a co-receptor for HIV-1. Its ligand, stromal cell-derived factor-1alpha (SDF-1alpha), affects neuronal viability. GTP binding protein (G-protein) linked signaling after neuronal exposure to SDF-1alpha, virus-infected monocyte-derived macrophage (MDM) secretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1alpha/beta was detected predominantly in astrocytes and at low levels in MDM. SDF-1beta/beta was expressed in HAD brain tissue and upregulated in astrocytes exposed to virus infected and/or immune activated MDM conditioned media (fluids). HIV-1-infected MDM secretions, virus and SDF-1beta induced a G inhibitory (Gi) protein-linked decrease in cyclic AMP (cAMP) and increase inositol 1,4, 5-trisphosphate (IP3) and intracellular calcium. Such effects were partially blocked by antibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protein-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These data, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD. |
| Databáze: | OpenAIRE |
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